Abstract. The oral administration of amphotericin B (AmB) has the major drawback of poor bioavailability. The aim of this work was to evaluate the potential of AmB-loaded cubosomes as an oral formulation with improved bioavailability. This manuscript firstly developed AmB-loaded cubosomes by using the SolEmuls technology. The encapsulation efficiency, the in vitro release, and stability studies in simulated gastrointestinal fluid were used to evaluate AmB-loaded cubosomes. The acute nephrotoxicity, bioavailability, and tissue distribution study of AmB-loaded cubosomes were assayed upon oral administration to rats. SAXS and cryo-TEM exhibited AmB-loaded cubosomes as a bicontinuous cubic liquid crystalline phase with Pn3m geometry. The encapsulation efficiency and the results of in vitro release and stability studies in simulated gastrointestinal fluid further demonstrated that AmB was successfully encapsulated in cubosomes. AmB-loaded cubosomal formulation orally administrated in rats did not show nephrotoxicity and its relative bioavailability was approximately 285% as compared to Fungizone®. The AmB-loaded cubosomal formulation presented an effective potential approach for enhancing the oral bioavailability of AmB.
In order to develop an oral formation of Amphotericin B (AmB) using phytantriol- (PYT-) based cubosomes with desirable properties, homogenization conditions were firstly investigated to determine their effects on the morphological and dimensional characteristics of cubosomes. Under the optimized homogenization conditions of 1200 bar for 9 cycles, cubosomes with reproducible, narrow particle size distribution and a mean particle size of 256.9 nm ± 4.9 nm were obtained. The structure of the dispersed cubosomes was revealed by SAXS (small-angle X-ray scattering) and Cryo-TEM (cryogenic transmission electron microscopy) as a bicontinuous cubic liquid crystalline phase with Pn3m geometry. To overcome the poor drug solubility and increase the drug-loading rate, a solubilization method was firstly used to develop cubosomes containing AmB. The encapsulation efficiency determined by HPLC assay was87.8%±3.4%, and UV spectroscopy and stability studies in simulated gastric fluids further confirmed that AmB was successfully encapsulated in cubosomes.
Rabeprazole sodium (RAB) dissolved in acidic media is accompanied by its degradation in the course of dissolution testing. To develop and establish the accumulative release profiles of ACIPHEX® Sprinkle (RAB) delayed-release capsules (ACIPHEX® Sprinkle) in acidic media using USP apparatus 2 (paddle apparatus) as a dissolution tester, the issues of determination of accumulative release amount of RAB in these acidic media and interference of hydroxypropylmethyl cellulose phthalate were solved by adding appropriate hydrochloric acid (HCl) into dissolution samples coupled with centrifugation so as to remove the interference and form a solution of degradation products of RAB, which is of a considerably stable ultraviolet (UV) absorbance at the wavelength of 298 nm within 2.0 h. Therefore, the accumulative release amount of RAB in dissolution samples at each sample time points could be determined by UV-spectrophotometry, and the accumulative release profiles of ACIPHEX® Sprinkle in the media of pH 1.0, pH 6.0, and pH 6.8 could be established. The method was validated per as the ICH Q2 (R1) guidelines and demonstrated to be adequate for quality control of ACIPHEX® Sprinkle and the accumulative release profiles can be used as a tool to guide the formulation development and quality control of a generic drug for ACIPHEX® Sprinkle.
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